Distal Renal Tubular Disorders Flashcards
what are two Na+ wasting disorders in the distal tubule?
- Bartter Syndrome
- Gitelman Syndrome
What distal tubule disorder causes HTN because of a defect in Na+ transport?
Liddle Syndrome
What percentage of Na+ is absorbed in the following areas?
- Proximal Tubule
- TALH
- Distal Tubule
- Collecting duct
Proximal Tubule = 65-70%
TALH = 25%
Distal Tubule = 5%
Collecting Duct = 1-2%
What is targeted by Acetazolamide and where?
Carbonic Anhydrase
- Proximal Convoluted Tubule
What is targeted by Furosemide?
- other drugs in this class?
Bumetanide, Ethacrynic Acid
- NK2C cotransporter in the TALH
What is targeted by Thiazides?
- where?
NC cotransporter in the Distal Convoluted tubule
What is the targeted by Amiloride?
- where?
- other drugs in this class?
Amiloride and Triamterene are in the same class
- ENaC **DCT and CD (I think the CD is more heavily targeted)
What is targeted by Spironolactone?
- other drugs in class?
- where?
Mineralcorticoid Receptor in the CD Eplerenone
General Bartter Syndrome (applicable to both types)
- 4 possible mutation?
- What are some key features of this syndrome?
- Inheritance?
- Treatment?
Mutations - AUTOSOMAL RECESSIVE:
Bumetanide-sensitive Na+-K+-Cl-cotransporter (NK2C - cotransporter), ATP-sensitive K+ channel (ROMK), Cl- channel A subunit (CLCNKA), Cl- channel B subunit (CLCNKB)
KEY FEATURES
- HYPOkalemia / HYPERaldosteronism => Hyperrreninemia
- HYPOcloremic metabolic alkalosis
- Kidneys showed hyperplasia of the juxtaglomerular apparatus
- Elevated plasma renin and aldosterone
Treatment: K+ supplements, Mg2+ supplements (if needed)
Differentiate Neonatal Bartter Syndrome and Classic Bartter Syndrome
- Common Features
- Key Differences
Common Features:
- Failure to Thrive
- Hypercalciuria
- Episodes of Dehydration
Key Differences:
NEONATAL - Polyhydramios, Preterm Delivery, NEPHROCALCINOSIS, HEARING LOSS
Classic - hypercalciurea but NO nephrocalcinosis
Gitelman Syndrome
- mutation, where?
- What are some key features of this syndrome?
Mutation:
AUTOSOMAL RECESSIVE mutation in NC (thiazide sensitive) Co-transpoerter on the LUMINAL side of the DISTAL CONVOLUTED TUBULE
Features:
HYPOkalemia and Hypochloremic Metabolic Alkalosis
May present with Dehydration and Tetany
HYPOcalicurecemia
What are some key distinguishing features between Bartter’s and Gitelman Syndrome?
- how does this relate to the nature of their mutation?
Bartter’s:
- HYPERcalciuria
- Mutation is in the TALH (NK2C, ROMK, or Cl- channel) which is MORE IMPORTANT for Na+ absorption - so deficiency here is more severe and disease is more severe…
- Failure to Thrive is more common
Gitelman’s Syndrome:
- *- HYPOcalciuria
- HYPERmagnesuria**
- Mutation is in the TSC/ NC cotransporter DCT which is less important for Na+ absorptoin
******All these syndromes of hypochloremic metabolic alkalosis have been associated with hyperplasia of the juxtaglomerular apparatus.
********Several other syndromes of hypochloremic metabolic alkalosis (chronic vomiting, diuretic abuse, congenital chloride diarrhea, cystic fibrosis, ingestion of formula deficient in chloride) can mimic Bartter and Gitelman syndrome. How might you distinguish them?
- *Liddle Syndrome**
- Mutation/inheritance?
- Clinical Disorder caused by mutation?
- Treatment?
Mutation:
- AUTOSOMEAL DOMINANT Gain of Function mutation in the Beta or Gamma subunit of Epithelial Sodium Channel ENaC
- *Clinical Disorder:
- Hyperabsorption of Na+ b/c of XS ENaC leads toHYPOkalemic Metabolic Alkalosis**
What happens when AVP binds the AVP-receptor?
- what specific receptor is most important?
AVPR2 receptor aka V2 receptors - its a GPCR
- causes cAMP release and PKA activation which phosphorylates vesicles and triggers them to fuse with the cell membrane
Why would hyperaldosteronsim and use of Diuretics lead to hypokalemia?
- *Diuretics:**
- Increase Na+ concentration in the Collecting Duct
- more exchange of Na+ through ENaC and potassium out of ROMK leads to increased K+ secretion
- *Hyperaldosteronism:**
- Increase of ENaC, ROMK, NKA, etc.
- More channels will favor the already favorable Na+ uptake
- *Nephrogenic Diabetes Insipidus (NDI)**
- Mutation(s)/ Inheritance(s)
- Pathophysiology
- DDx technique
Mutations:
- *AVPR2 (RECEPTOR MUTATION)** - X-linked point mutations (XQ28)= 90%
- *AQUAPORIN-2** - Autosomal Recessive = 10%
Pathophysiolgy:
- *LOW urine Osmolarity** - b/c aquaporins are needed to concentrate the urine
- *CRAZY HIGH THIRST** - PLASMA osmolarity is HIGH water is not being reabsorbed
DDx:
- This and Central Diabetes Insipidus present the same way except a person with Nephrogenic Diabetes insipidus should be responsive to ADH/DDAVP injection
How do patients with NDI (nephrogenic diabetes insidpidus) present?
- additional problems in infants?
- Treatment?
Symptoms:
- Polydipsia, Polyuria, Irritability, Constipation
- Formula Intolerance with Vomiting, Failure to Thrive, Hyperthermia
Signs:
- Hydronephrosis
- Megaureter
- Bladder Dysfunction
Infants:
- Severe dehydration can lead to hypoperfusion of the Brain, Kidneys
- may cause MENTAL RETARDATION and Renal Damage
TREATMENT:
- *- Abudnant Free Water Intake
- Low Solute Diet
- Diuretics**
What diuretics are typically used in nephrogenic diabetes insipidus?
- what is the point of using diuretics to treat these patients?
Diuretics:
- Amiloride and Hydrochlorothiazide
Purpose:
- Reduce Obligatory urine ouput to prevent episodes of Dehydration (leading to reduced risk of mental retardation)
What is Glucocorticoid-Remediable Hyperaldosteronism (GRA)?
- Mutation?
- Pathiophysiology/disease caused? (hyper/hypo kalemia/natremia etc.)
- Treatment?
Mutation:
- Results from the recombination of the homologous genes for 11-beta-hydroxysteroid dehydrogenase (11betaHSD) and aldosterone synthase
Pathophysiology:
- Gene pdt. = hybrid molecule that MAKES ALDOSTERONE in response to STRESS
- causes LOW RENIN HTN and HYPOKALEMIA
Treatment:
- Physiologic doses of Glucocorticoids
- *Apparent Mineralocorticoid Excess**
- Mutation
- Pathophsiology? (hyper/Hypo kalemia/natremia etc.)
- Treatment?
Mutation:
- Kidney isozyme of 11betaHSD
Pathophysiology:
- increased levels of cortisol in the kidney cross-reacts and **activates the mineralcorticoid receptor
- causeslow renin HTN, andHYPOKalemia**
Treatment:
- Physiologic Doses of Glucocorticoids
How do Hypoaldosteronism and Pseudohypoaldosteronism come about?
- do they cause hypo or hyperkalemia?
- *Hyperaldosteronism:**
- Congenital Adrenal Hypoplasia
- Congenital Adrenal Hyperplasia
- Autoimmune
- *Pseudohypoaldosteronism (PHA):**
- PHA Type I
- PHA Type II
- Tubular Injury (obstructive uropathy)
*****BOTH CAUSE HYPERKALIEMIA******
What syndrome is the “mirrow image” of Liddle syndrome?
• Why can we say this?
Pseudohypoaldosteronism (PHA) type I
Characterized by:
- *1. Hyperkalemia
2. Hyponatremia**
3. Prone to severe volume depletion and HYPOTENSION
What is the inheritance of PHA type I?
• Treatment?
- *PHA type I - Any Type of Inheritance**
- *• Recessive Form** = ENaC mutation (explains the hyperkalemia with Hyponatremia)
Treatment:
• High Salt Diet, Prompt Fluid Resusciation (Na+ containing fluids are used in the case of volume depletion), K+ Binding Resin May also be Needed
PHA (pseudohypoaldosteronism) Type II
• AKA?
• Genetic Defect/Pathophysiology?
• Area of filtration system affected?
PHA II aka Gordon Syndrome
Genetic Defect:
• WNK1 and WNK4 are mutated leading to INCREASED absorption into the Elecroneutral Na/Cl transporter in the Distal Convoluted Tubule
Pathophysiology:
• Result is excessive Na+ reabsorption and HTN
• K+ secretion is reducedbecause less Na+ is delivered to collecting duct
What syndrome does Gordon Syndrome mirror?
• Treatment for Gordon Syndrome?
Gordon’s is the mirror image of Gittelman’s Syndrome
Treatment: THIAZIDE DIURETICS work to treat Gordon’s because they tone down the over active NC co-transporter in the DCT.
T or F: Both PHA-I and PHA-II are associated with Hyperchloremic Metabolic Acidosis.
True
What is a major sign that separates PHA Type I and Type II?
PHA Type I - associated with Hypotension
PHA Type II - associated with Hypertension
What type of RTA (renal tubule acidosis) is associated with PHA types I and II?
• what defines this type of RTA?
- HYPERchloremic Metabolic Acidosis and HYPERkalemia resulting from a deficiency or an inability to respond to aldosterone action
- pH of urine may be less than 5.5. during acidosis
What are some etiologies of Type IV RTA (renal tubule acidosis)?
Primary Mineralcorticoid Deficiency
• Addisons’s, Adrenal damage, 21-hydroxylase deficiency
Secondary Mineralcorticoid Deficiency
• Hyporeninemic, Hypoaldosteronism ass’d with Diabetic nephropathy, AIDS,
- *Mineralocorticoid Resistance**
- *• PHA type I and II**
Renal Tubular Dysfuncion
• Lupus Nephritis, Obstructive uropathy, Hyperkalemic Distal RTA
What is a means of testing for Type IV Renal Tubular Acidosis?
• what is this test assessing?
TTKG - Transtubular Potassium Gradient
• Test assess the Aldosterone activity in the Kidney
How is TTKG (transtubular potassium gradient) calculated?
• What are the cutoffs and what do they tell you?
TTKG = ([K]urine/[K]plasma)) / (U/P)osm
Hypokalemia TTKG SHOULD BE less than 2 (Denotes Appropriately Decreased Mineralocorticoid activity)
Hyperkalemia TTKG SHOULD BE Greater than 10 (denotes appropriately increased mineralocorticoid activity)
Someone is hypERkalemic but has a TTKG of 4.0.
• What general Problem is likely present?
• 3 different problems might you expect?
This Person has a TTKG of 4.0 which means that are not concentrating urine well enough in the presence of HYPERKALEMIA
- This means there must be a general problem with ALDOSTERONE - this is because aldosterone responds to High K+ concentrations by upregulating ENaC, POMK, etc. which aid in K+ excretion
- Problem could be occuring at 1 of 3 levels:
- Aldosterone is never made - Adrenal Insufficiency
- Low Renin Secretion - Hyporeninemic Hypoaldosteronism
- Tubular Resistance - messed up tubules that can’t respond correctly
How would you differentiate Hyperkalemia due to:
• Adrenal Insufficiency
• Hyporeninemic Hypoaldosteronism
• Tubular Resistance
Adrenal Insufficiency:
• Plasma Renin will be high but no Aldosterone will be secreted
Hyporeninemic Hypoaldosteronism:
• Low Plasma renin AND low plasma Aldosterone
Tubular Resistance:
• Increased Plasma renin and aldosterone concentration in both
T or F: in all cases of Renal Tubular Acidosis the person have hypochloremic metabolic acidosis with an abnormal ion gap.
FALSE - RTA = HYPERchloremic metabolic acidosis with a NORMAL PLASMA ANION GAP.
What are the ONLY three causes of acidosis with a Normal Plasma anion gap???
- Renal Tubular Acidosis
- Exogenous Chloride (giving someone a bunch of a chloride containing salt e.g. arginine hydrochloride)
- GI bicarbonate Loss - DIARRHEA
Type II Renal Tubule Acidosis
• cause?
• Associations to KNOW!
• Key features
Type II RTA:
• PROXIMAL TUBULE defect leading to decreased Bicarbonate Reabsorption
Association:
• almost always associated with FANCONI SYNDROME
Key Features:
• Pts. can achieve a urine pH less than 5.5 in the face of low bicarb
Formula For Anion Gap used to look at acidosis
• Normal for Kids? Adults?
Formula: Na+ - (Cl- + CO2)
Normal for Kids: 8-20
Normal for Adults: 10-12
What is a key feature to differentiate Type I and Type IV RTA?
Type I RTA: can’t concentrate urine past pH 5.5 even in acidosis
Type IV RTA: can concentrate urine below pH 5.5. in acidosis
Type I (classical distal) RTA
• cause?
• Inheritance?
Cause: Impaired AMMONIUM EXCRETION and impaired excretion of titratable acid
Inheritance: Sporadic or Autosomal Dominant
How do patients with Type I RTA present?
• Symptoms
• Lab Findings
Symptoms:
• Polyuria, Dehydration, Constipation
• Short Stature, Failure to thrive
Lab Findings:
• HYPERCHLOREMIC, HYPOKALEMIC, METABOLIC ACIDOSIS
• low pH, low serum Bicarbonate, hypokalemia, hyperchloremia
• URINE pH between 6.0 and 7.0
• Decreased urinany citrated excretino and Hypercalciuria
What is a common complication of Type I (classical distal RTA)?
• Treatment
**Nephrocalcinosis can lead to stones later in life
Patients may also get rickets or osteomalacia
Treatment:**K+ and Bicarbonate Supplements
What are some causes of Elevated Anion Gap Acidosis?
- Ketoacidosis
- Lactic Acidosis
- Inborn errors of Metabolism (causing acidemias)
- Poisons (MeOH, Et. Glycol, Salicylates etc.)
T or F: Type I (proximal) RTA is almost always associated with Fanconi syndrome (more later)
False, Type I (classical distal) RTA is very rare and presents with hypokalemia, hypercalciuria, nephrolithiasis, and failure to thrive
T or F: Type IV (hyperkalemic) RTA is a syndrome of aldosterone deficiency or unresponsiveness
True
T or F: RTA almost never presents with Diarrhea
True
T or F: Type II (proximal) RTA is almost always associated with Fanconi syndrome
TRUE
What 4 tests should you look for in RTA?
- Fractional Excretion of Bicarbonate
- Urine pH
- Urine Anion Gap
- U-B PCO2
How do you calculate the Fractional Excretion of Bicarbonate?
• how can you differentiate the type of RTA by looking at this?
FEHCO3 = (Ubicarb x Pcreatinine) / (Pbicarb x Ucreatinine)
- Greater than 10-15% in Proximal RTA II
- Less than 5% in Classical RTA I
- Less than 5-10% in hyperkalemic RTA IV
How can urine pH differentiate the 3 types of RTA?
Greater than 5.5 it MUST be classical distal RTA
Less than 5.5 it could be either type II or Hyperkalemic (type IV) RTA
How is URINARY Anion gap calculated?
• what does it tell you about the different types of RTA?
URINARY anion Gap = UAG = (Na + K) - Cl
• IF GAP is a negative number this indicates the presence of increased ammonium
• UAG POSITIVE in: Type I and IV
• UAG NEGATIVE in: Type II
What is U-B pCO2?
• what is it looking for?
• explain the physiology ?
• what is a normal test result?
U-B PCO2:
• Patient is given bicarbonate or acetazolamide (carbonic anhydrase inhibitor) causing bicarbonaturia
• IF DISTAL TUBULE can secrete H+ ion then HCO3- is neutralize and CO2 is generated
• Normal people can generate a gradient of 10-15 mmHg
What type of RTA lead to a decreased U-B pCO2?
Types I and IV because there is less little/no neutralization by H+.
Characterize the following for RTA type II:
Finding
Plasma K+
Urine pH
Urine Anion Gap
U-B PCO2
FE HCO3-
Associated Findings
Plasma K+: Low
Urine pH: Less than 5.5
Urine Anion Gap: Positive
U-B PCO2: normal
FE HCO3-: Greater than 15%
Associated Findings: Fanconi Syndrome
Characterize the following for RTA type I:
Plasma K+
Urine pH
Urine Anion Gap
U-B PCO2
FE HCO3-
Associated Findings
Plasma K+: Low
Urine pH: greater than 5.5
Urine Anion Gap: Positive
U-B PCO2: Low
FE HCO3-: Less than 5%
Associated Findings: increased Urinary Ca2+
Characterize the following for RTA type IV:
Plasma K+
Urine pH
Urine Anion Gap
U-B PCO2
FE HCO3-
Associated Findings
Plasma K+: High
Urine pH: Variable
Urine Anion Gap: Positive
U-B PCO2: Low
FE HCO3-: Less than 5-10%
Associated Findings: Renal Insuffiency in some people
WHY IS JUXTAGLOMERULAR HYPERTROPHY SEEN IN BARTTER SYNDROME?
• what is Bartin?
Bartter Syndrome = Defective NK2C, ROMK, Cl- channel A or B subunit, Barttin (needed for insertion of Cl- channel of A and B subunits into kidney cells and the inner ear)
Hypertrophy because RENIN is persistently secreted because there is never any response by the tubule cells to the aldosterone that gets produced
T or F: people with Bartter syndrome have huge salt cravings.
TRUE - they will crave things like pickle juice to make up for their salt intake
***Note: they treat Barter Syndrome pts. with Potassium Supplements to prevent the formation of Renal Cysts***
Why do we see polyhydramnios in Bartter Syndrome that presents prenatally?
- what chemical will be high in the amniotic fluid?
- why would you give these kids cyclooxgenase inhibitors at birth?
These patients lack the channels necessary to concentrate the urine
- PGE2 will be high in the amniotic fluid
- COX inhibitors like indomethicin Reduces Urine output so the kids don’t drink as much and fill up on H2O and they will eat more
Compare and Contrast the severity of Bartter’s and Gitelman syndrome?
Gitelman Syndrome is much LESS severe than Bartter’s (because an area of much less Na+ absorption is affected - aka DCT) - people can live with Gitelman and never know that they have it.
Why do people with Liddle Syndrome present with LOW RENIN?
These people have an ENaC GAIN OF FUNCTION leading to increased water absorption and HTN. Renin is down regulated in the face of this HTN.
What condition can be caused secondary to Pyloric Stenosis?
HYPERALDOSTERONISM - caused by volume depletion leading to increased renin and increased Aldosterone
Hyperkalemia is most often associated with kidney failure but in people with PHA type I its also present. Explain this.
Disease caused by:
- Mutation in Mineralcorticoid Receptor (dominant)
- Loss of Function mutation in ENaC (recessive)
Either Way these patients lack the Na+ and K+ exchange mechanism found in the DCT leading to too much K+ reabsoption
What is the MOST important test to run when considering whether someone has RTA?
Urine anion Gap
What are the Principle Urinary Cations and Anions?
Cations: Na+ and K+
Anions: NH4+
